Project 6 proposes clinical trials testing new therapeutic strategies designed to reduce the morbidity, non- leukemic mortality and incidence of relapse associated with allogenic hematopoietic cell transplants (HSCT) applied to the treatment of acute leukemias and myelpdysplastic syndromes (MDS), particularly in older patients and in patients lacking an HLA-matched sibling donor. The project includes 8 clinical trials organized under 3 specific aims. Specific aim 1 includes 2 phase II clinical trials testing the potential of keratinocyte growth factor (KGF) to reduce transplant-related mortality and enhance DPS by reducing early toxicity and stimulating thymopoiesis and T cell reconstitution in adults (median age >50)with hematologic malignancies receiving HLA- matched or 1-2 allele disparate CD34+ E- T cell depleted PBSC grafts from related or unrelated donors after treatment with myeloablative conditioning regimens developed in this grant period. Specific Aim 2, proposes two trials of double unit cord blood transplants,the first (Aim 2A) a trial of double UCBT myeloablative conditioning to patients with acute leukemias, MDS and advanced NHL who lack an 8-10 allele related or unrelated donor; the second (Aim 2B) a trail of double UCBT administered after a novel nonmyeloablative regimen including Rituximab in patients with lymphomas responsive to a GVL effect. These trials each include correlative analyses designed to identify cord blood graft and host features that determine the selective engraftment of 1 UCBT in a given allogenic host. As developed in this center, TCD marrow or PBSC transplants have achieved consistent engraftment with a low incidence of GVHD without use of post-transplant drug prophylaxis. Effective prevention of GVHD thus allows us to critically examine adoptive cell therapies and immunostimulatory cytokine in the absence of concurrently administered immuno-suppressive drugs or biologicals. Specific Aim 3 addresses this objective in 3 trials. Aim 3A is a phase I trial of T cells sensitized by a new technique employing overlapping 15-mer peptides spanning CMV-pp65 for treatment of patients with persistent CMV viremia or infection. In Aim 3B, we propose a phase I trial of T cells sensitized with overlapping 15-mer peptides spanning the sequence of the WT1 protein for treatment of patients with minimal residual disease or recurrence of WT-1 + acute leukemias, MDS and blastic CML post transplant. Aim 3C proposes a pilot phase II trial of adoptive therapy with in vitro isolated, HLA haploidentical NK cells following stem cell-sparing chemotherapy for patients relapsing in the first year post transplant with AMI, ALL and blastic CML. Relevance to Public Health: These trials test novel transplant strategies which show promise of improving prospects for sustained DPS in adults with acute leukemia, MDS and lymphoma, particularly older patients and patients lacking a matched sibling donor. They will also test adoptive therapies which may be broadly applied to patients with severe viral infection or leukemia relapse.